GEN News Highlights

The Next New Thing in Curbing Cholesterol May Be Sortilin

Structure of sortilin, a protein encoded by the hypercholesterolemia-risk gene SORT1. The image is based on PyMOL rendering of PDB 3F6K. [Pleiotrope]

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Although it is being developed at breakneck pace, the PCSK9 class of drugs may soon be followed by yet another sort of cholesterol-fighting drug. This new, new class of drugs would work a bit upstream of the class based on inhibiting PCSK9, or proprotein convertase subtilisin/kexin type 9. Specifically, it would target a stretch of intracellular pathway through which PCSK9 must pass before it can be activated and secreted into the bloodstream. It would, in a sense, cut PCSK9 “off at the pass,” and thereby reduce so-called bad cholesterol.

The idea of pursuing a new class of drugs was inspired by work characterizing sortilin, which has been suspected of playing a role in cholesterol metabolism. It turns out that sortilin is a PCSK9 sorting receptor. This finding was established by researchers at Aarhus University, who assert that sortilin colocalizes with PCSK9 in the trans-Golgi network and facilitates its secretion from primary hepatocytes.

The researchers published their results February 4 in Cell Metabolism, in an article entitled “The Hypercholesterolemia-Risk Gene SORT1 Facilitates PCSK9 Secretion.” In this article, the authors indicated that “sortilin-deficient mice display decreased levels of circulating PCSK9, while sortilin overexpression in the liver confers increased plasma PCSK9.” The authors added that “circulating PCSK9 and sortilin were positively correlated in a human cohort of healthy individuals, suggesting that sortilin is involved in PCSK9 secretion in humans.”

One of the authors, Camilla Gustafsen, a postdoc at Aaarhus University, said, “If we inhibit sortilin what we have seen is that this has the same effect as if we inhibit PCSK9 itself. In other words—much less bad cholesterol. This opens the way for a completely new strategy for treating increased cholesterol.”

Circulating PCSK9, scientists learned, destines low-density lipoprotein receptor for degradation in lysosomes, resulting in increased LDL cholesterol. PCSK9, then, became a compelling target—so compelling, in fact, that work on PCSK9 drugs forged ahead even though PSCK9’s complex mechanism of action remained poorly understood. Now, however, just as PSCK9-based drugs are nearing approval, mechanistic details about the intracellular trafficking of PSCK9 are emerging.

“All eyes have been on PCSK9 for 10 years. Now we present a new discovery, which contributes to the understanding of PCSK9 and can, at the same time, pave the way for a treatment that apparently has the same effect as PCSK9 inhibitors,” commented Simon Glerup, associate professor at Aarhus University. “The PCSK9 market is already limited by patents and copyrights, so this can make it possible for new pharmaceutical companies to enter the scene for the benefit of the patients.”

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